Visible‐Light‐Induced Radical Di‐ and Trifluoromethylation of β, γ‐Unsaturated Oximes: Synthesis of Di‐ and Trifluoromethylated Isoxazolines

Abstract

The visible‐light‐promoted difluoromethylation and trifluoromethylation/cyclization of β, γ‐unsaturated oximes has been successfully accomplished with fluorinated sulfones as the difluoromethylation and trifluoromethylation reagents. The reaction was proposed to proceed through a sequence comprising CF2X‐radical generation, fluoromethyl radical addition, single electron oxidation, and intramolecular cyclization to afford the corresponding di and trifluoromethylated isoxazoline derivatives in an overall redox‐neutral process.

Radical C–H 18F-Difluoromethylation of Heteroarenes with [18F]Difluoromethyl Heteroaryl-Sulfones by Visible Light Photoredox Catalysis

“…These results suggest the involvement of radical intermediates in the present photocatalytic C-H 18 F-difluoromethylation reaction. On the basis of these observations and previous research works reporting photoredox C-H difluoromethylation reactions with the sulfones 1 [39][40][41][42][43][44] and 2 [45], a general and simplified reaction mechanism is shown in Figure 7. The proposed mechanism for the C-H 18 F-difluoromethylation of heteroarenes 7a-7g involved the reduction of the [ 18 F]difluoromethyl heteroaryl sulfones ([ 18 F]5a, [ 18 F]5c, and [ 18 F]5f), via an oxidative quenching of the photoexcited fac-Ir III (ppy)3, to generate the [ 18 F]CF2H radicals.…”

“…In 2016, Hu and Fu reported the use of difluoromethyl benzothiazolyl-sulfone (1) in the radical C-H difluoromethylation of biphenyl isocyanides [39] and olefinic amides [40], respectively. The reagent 1 was also employed in the preparation of CF2H-substituted heterocycles of biological relevance, including isoquinolinediones [41], coumarins [42], isoxazolines [43], and oxindoles [44]. In 2019, Liu and co-workers developed a procedure for C-H difluoromethylation of N-arylacrylamides with the reagent difluoromethyl pyridyl-sulfone (2), under visible light photoredox conditions [45] ( Figure 1B).…”

“…[37,38]. (B) Application of the difluoromethyl sulfones 1 and 2 in the preparation of heterocycles of biological relevance, under visible light photoredox catalysis [39][40][41][42][43][44][45].…”

“…To the best of our knowledge, the effectiveness of the non-radioactive references of these novel [ 18 F]difluoromethyl heteroaryl-sulfones in photoredox C-H difluoromethylation has never been described in the literature. Application of the difluoromethyl sulfones 1 and 2 in the preparation of heterocycles of biological relevance, under visible light photoredox catalysis [39][40][41][42][43][44][45].…”

Photocatalytic Difluoromethylation Reactions of Aromatic Compounds and Aliphatic Multiple C–C Bonds

“…Then, water attacks the carbocation III (Scheme 34) and is followed by deprotonation, which affords the spirooxindole hemiaminal IV (Scheme 34) that it is finally oxidized by the addition of PCC in the same pot, generating the reaction product. A practical method for the synthesis of difluoromethylated isoxazolines through visible-light induced radical difluoromethylation of β,γ-unsaturated oximes has been published by Zhu et al [81]. The reaction employs an aromatic ketone-derived β,γ-unsaturated oxime as a substrate, a difluoromethylsulfone (2-((difluoromethyl)sulfonyl)benzo[d]thiazole) as the CF2H source, NaHCO3 as the base, and Ir(ppy)3 as the photocatalyst in acetonitrile as the solvent, irradiated with blue LEDs (Figure 6).…”